Davis left with a first-quarter concussion and the 49ers trailing 14-0. That deficit had grown to 28-6 by the time Manningham suffered a third-quarter knee injury.

Davis' injury occurred when he got leveled by safety Kam Chancellor on a potential first-quarter reception at the Seahawks' 2-yard line. Coach Jim Harbaugh said Davis informed him it's a "mild" concussion and that "he said he felt better."

Chancellor drew a 10-yard, unnecessary-roughness penalty, and the 49ers thus had first-and-goal at the 10-yard line. The series ended with Richard Sherman's 90-yard touchdown return of a blocked, 21-yard field goal attempt by David Akers.

Davis, who's started the past 90 games dating back to 2007, made a 27-yard catch earlier in the drive to bring the 49ers into Seahawks territory for the first time.

Manningham injured his left knee while being tackled on the 49ers' opening series after halftime. Linebacker Leroy Hill drove his helmet into Manningham's knee on the reception, which Manningham then fumbled at the Seahawks' 40-yard line.

Harbaugh said X-rays were negative on Manningham, who missed the previous two games because of a shoulder injury.

Justin Smith didn't suit up for the first time in 190 games, ending the NFL's third-longest streak among active players. The mainstay defensive lineman also will miss the 49ers' regular-season finale before potentially returning in the playoffs, according to an ESPN report citing a league source.

Smith did not practice last week after injuring his left elbow in the 49ers' 41-34 win at New England on Dec. 16. Ricky Jean Francois started in place of Smith, who was in attendance and wore no visible arm brace.

"Not having Justin is a huge deal," safety Donte Whitner said. Added linebacker Ahmad Brooks: "You felt it all week. It just felt different. You always hear him out there."

Cornerback Tarell Brown hyperextended his right knee by landing awkwardly after jumping over teammate Ray McDonald in the second quarter. Brown missed about 10 plays before returning. "It went numb," Brown said, "but it's part of the game."

Aldon Smith didn't produce a sack for the second straight game and fell out of the league lead. His franchise-record 19½ are one less than the Houston Texans' J.J. Watt.

Asked how Justin Smith's absence affected him, Aldon Smith said: "I wouldn't say I was doubled more. They saw Justin was not there and they tried to take advantage of it."

Running back Frank Gore had five of his six carries in the first quarter and finished with a season-low 28 yards. "We had to do it," Gore said of abandoning the run game. "They got up so fast, we had to try different things."

Former Stanford products Richard Sherman and Doug Baldwin had big games for the Seahawks. Sherman had an interception and returned a blocked field goal for a touchdown. Baldwin had four receptions for 53 yards and two touchdowns.

Sherman started at cornerback two days after reportedly attending an appeal hearing in New York regarding a potential four-game suspension for performance-enhancing drug use. After the game, he said there was a "chain of custody" mistake that led to his positive test and was the basis of his appeal.